A number of therapeutic amine compounds have been developed for the treatment of psychiatric, neurologic and metabolic disorders including, but not limited to, depression, obesity, fibromyalgia, neuropathic pain, restless leg syndrome, attention deficit hyperactivity disorder (ADHD), migraine, pain, sexual dysfunction, Parkinson's disease, Alzheimer's disease, anxiety, narcolepsy-cataplexy syndrome, seizures or drug/substance addiction/cessation. These include bupropion hydrochloride salt, [1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone.HCl] which is the active ingredient of WELLBUTRIN®. It is marketed in the United States for the treatment of depression. Bupropion hydrochloride is also the active ingredient of ZYBAN®, which is marketed in the United States as an aid to smoking cessation.
The compound (+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol hydrochloride salt, which is an active metabolite of bupropion hydrochloride, is the active ingredient of radafaxine, and is proposed for the treatment of depression, obesity and other conditions. (U.S. Pat. No. 6,274,579 and U.S. Pat. No. 6,391,875). Another therapeutic amine compound, for example, (2S,3S,5R)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol, the active ingredient of manifaxine, has been proposed for the treatment of depression, among other ailments (U.S. Pat. No. 5,104,870).
Bupropion, however, is known to cause seizures in high therapeutic doses (Harris, et al., Fatal bupropion overdose, J. Toxicol. Clin Toxicol. (1997) 35: 321-4; Kuate, et al., A. Bupropion-induced epileptic seizures, Rev. Neurol. (2004), 160: 701-3.) Several therapeutic amines, including bupropion and radafaxine, are known to elicit seizures in animals (U.S. Pat. No. 6,274,579; and U.S. Pat. No. 6,391,875; see also Shepard, Pharmacotherapy (2005) 10: 1378-82). Other undesirable side effects may also occur in the administration of therapeutic amine compounds and such compounds may be considered in trials conducted for potential abuse liability. Thus, such compounds may be under-utilized at administration dose maximums, even if favorable treatment outcomes are possible.
To the extent these and other therapeutic amine compounds exhibit undesirable side effects, compounds and/methods of treatment which avoid such side effects would be advantageous. The conjugate compounds and methods disclosed herein provide such advantages.